A variety of cytokines utilizes Janus kinase (JAK) and the signal transducers and activators of transcription (STAT) family of transcription factors, to exert their biological functions. The tyrosinephosphorylated STATs form homo- or heterodimers and translocate into the nucleus, then activate target genes. Compared with other kinases, little is known about cellular regulators of the JAKs. The CIS (cytokine-indelible SH2 protein) family of proteins that w found recently has been implicated in regulating signal transduction by a variety of cytokines, The first member of this family, CIS1 was cloned as an immediate early gene responding to a number of cytokines including erythropoietin (EPO), interleukin 2 (1L2), 1L3 and GM-CSF, and is regulated by STAT5. CIS1 binds to the tyrosine phosphorylated IL3 and EPO receptors, and negatively regulates STAT5, The second family member was independently cloned by three groups and is termed JAB, SOCS-1, or SSI-1 (6, 20, 29). JAB is induced by IFNgam
… Morema and inhibits lFN as wellas IL6 signaling. JAB and CIS directly bind to the kinase domain of JAKs, thereby inhibiting the kinase activity. In collaboration with Dr. Ihie's group, we already created JAB and CIS3 genes knockout mice and we are analyzing them now. We demonstrate that JAB specifically binds to the tyrosine residue (Y1007) in the activation loop of JAK2 whose phosphorylation is required for activation of kinase activity. An additional N-terminal 12 amino acid region (kinase inhibitory region) of JAB also contributes to high affinity binding to the JAK2 tyrosine kinase domain and is required for inhibition of JAK2 signaling and kinase activity. Our studies define a novel type of regulation of tyrosine kinases and might provide a basis for the design of specific tyrosine kinase inhibitors, On the other hand, it has not been clear how CIS1 suppresses STAT5 activation. We reported that CIS1 binds to the region of the EPO receptor containing the second tyrosine residue (Y401). One of the mechanisms is simply masking the STAT5 binding sites on the receptor. The other possibility is that CIS1 accelerates degradation of the receptor-CIS1 complex by the ubiquitin-proteaspme pathway. Further study is necessary to elucidate the mechanism of STAT5 inhibition by CIS1. Less